Monday, April 22, 2013

The active drug in Tylenol, acetaminophen, is one of the best medications we have for helping people in pain. It's also one the most commonly overdosed substances in the world and puts about 60,000 Americans in the hospital every year. Several hundred people in the U.S. will die in 2013 from liver failure after acetaminophen overdose.

Tylenol isn't addictive like narcotics, and the kids don't take it to get high, which lends it an air of benignity and social acceptance not otherwise afforded to many pain medications. When people overdose on pills like Vicodin or Percocet, though, which contain acetaminophen, it's that component that often does the most damage.

kate*/flickr

Acetaminophen is also more accepted in that we don't think of Tylenol as altering our mental state. People can take it and still drive a car and go to work and remain fully present beings. But the more it's studied, the more it seems we may be overlooking subtle cognitive effects. In 2009, research showed that it seemed to dull the pain of social rejection -- sort of like alcohol or Xanax. The author of that study, Nathan DeWall at the University of Kentucky, said at that time, "Social pain, such as chronic loneliness, damages health as much as smoking and obesity."

New research this week found that Tylenol altered the way subjects passed moral judgments. Psychologists used that as a proxy measure for personal distress, a relationship that has been previously demonstrated.

Daniel Randles and colleagues at the University of British Columbia write in the journal Psychological Science, "The meaning-maintenance model posits that any violation of expectations leads to an affective experience that motivates compensatory affirmation. We explore whether the neural mechanism that responds to meaning threats can be inhibited by acetaminophen." Totally.

More plainly, "Physical pain and social rejection share a neural process and subjective component that are experienced as distress." That neural process has been traced to the same part of the brain. They figure that if you blunt one, you blunt both. As they told LiveScience, "When people feel overwhelmed with uncertainty in life or distressed by a lack of purpose, what they're feeling may actually be painful distress ... We think that Tylenol is blocking existential unease in the same way it prevents pain, because a similar neurological process is responsible for both types of distress."

In this study, Randles' team gave 120 people either two extra-strength Tylenol or a placebo. They then primed them by asking half to write about what happens when we die (meant to invoke or replicate existential anxiety) and the other half to write about a control, non-existential topic (going to the dentist, meant to focus people on concrete things). The rationale was that "thinking about death is incompatible with everyday thoughts ... and that it leads to the same anxiety ... as frustrated social interactions or perceived incongruities."

Then all were asked how high they would set bond for a hypothetical person arrested for prostitution.

Randles et al, Psychological Science

Among people who took the placebo pill, those who wrote about existential anxiety set much higher bail ($450) than those who wrote about the dentist ($300). But if they took Tylenol and wrote existentially, that sense of moral judgment seemed to be blunted. They set the same bond regardless of the priming.

Then in a similar, separate experiment, they primed the subjects by having them watch video clips. They either watched The Simpsons or a film by surrealistic neonoir writer/director David Lynch, in which humans with rabbit heads wander an urban apartment muttering non sequiturs. They then passed judgment on people arrested in a hockey riot. Again, the people in the existential mindset imposed harsh sanctions, but the people who'd watched The Simpsons were lenient. If they'd taken Tylenol first, though, the David Lynch-induced anxiety was apparently blunted. They recommended the same sanctions as the Simpsons-primed group.

This all raises more questions than it answers. This study was small. Theheadlines are grandiose. The way people pass moral judgments is not necessarily indicative of their level of existential anxiety. But acetaminophen indeed appears to be affecting people's perspectives, which further muddies our already complex relationship to the drug.

As Randles sees the value of their findings, "For people who suffer from chronic anxiety, or are overly sensitive to uncertainty, this work may shed some light on what is happening and how their symptoms could be reduced."

Even though these changes in judgment are abstract and seemingly for the better, inclining people to benevolence and forgiveness, what other cognitive effects of acetaminophen might we yet discover? For the millions who take acetaminophen on a semiregular basis unaware that it might be confounding their value system, as well as the artists whose livelihoods are contingent on their work invoking profound existential angst, the question is not just academic.

Sunday, April 21, 2013

Children's Pain Medicine Care Complex is one of only a few programs in the country focused exclusively on managing pain for infants, children, and teens. When children are unable to express their pain in words, our pediatric specialists have the unique insight to help.

Our multidisciplinary approach enables us to treat your child's physical symptoms as well as the psychological and emotional aspects of pain. We consider how a child feels and perceives pain, and take steps in care to reduce their fears and their family's anxieties.

Conditions We Care For There is no typical pain patient. The team looks at every part of a child's pain. We develop a unique treatment plan that may blend traditional medicine and alternative therapies to best fit the needs of each patient.

The team helps children affected by long-term pain, usually lasting 4 to 6 weeks, who have not responded to standard treatments, and patients with certain conditions, including:

Psychological therapy is an important part of the comprehensive care we provide to patients and their families. Children and teens with chronic pain often miss out on activities they enjoy, like hanging out with friends or playing sports. The absence of such normal childhood connections can affect a child's well-being, and additional support from our team can help you and your child cope.

Successful treatment for complex pain involves the whole family and the community around the patient. Your child's care team includes your child's primary care doctor, our specialists, as well as you, your child, and your family.

We work with you and your child to develop an individual approach for treatment. This includes:

• Pain Behavior Assessment and Disability Evaluation Because every child reacts to pain differently, we evaluate the physical pain, how your child thinks about the pain, and how the pain impacts interactions with friends, family, and life in general.

• Cognitive Behavioral Therapy As part of treatment, we use cognitive behavior therapy to help a patient think differently about pain. For many children, this approach effectively reduces pain, disability, and distress. Together, we set goals and gradually increase activity levels so your child can become more active and enjoy a normal childhood as much as possible. Support for Patients and Families Ongoing pain impacts a child physically, emotionally, and socially, and it involves the entire family. The Pain Medicine Care Complex team is available 24 hours a day to assist families through urgent pain crises. A treatment plan engages everyone in a child's life as an active participant in the healing process, from the child's parents and siblings to the primary care doctor and teachers.

This collaboration between programs means that we offer the most advanced therapies for patients. The Institute's Pain Medicine Initiative is one of the leading research centers in the country, developing new medications and interventions to safely and effectively reduce pain for our young patients.

WASHINGTON — Fifteen-year-old Reilly woke up one morning with a sharp, stabbing pain in his left leg that soon spread to other parts of his body. The pain, which started early last year, forced him to quit soccer, and he spent the next four months being poked, prodded and scanned by doctors.

The test results were inconclusive. "No one could tell him why he was in a ball on the floor unable to function," said Nina, his mother, who agreed to be interviewed only on the condition that the family's surname be withheld.

Finally, last June, Dr. Sarah Rebstock, a pediatric anesthesiologist at Children's National Medical Center, gave Reilly a diagnosis of chronic regional pain syndrome. The nerve disorder is characterized by chronic and severe burning pain, pathological changes in bone and skin, excessive sweating, tissue swelling and extreme sensitivity to touch.

The sight of the teenager reaching in the air and shuffling from side to side as his on-screen avatar hurled down an intergalactic tube racking up rings and gems seemed unremarkable. After all, game consoles like Microsoft's Xbox and Nintendo's Wii have become ubiquitous in American households, and many hospitals and clinics use them to add an element of fun to physical therapy.

But TubeRunner is one of four of galaxy-themed video games created specifically for this complex, where pain specialists and game developers are piloting an approach to measuring pain. Dr. Julia Finkel hopes that using technical data from games and interactive activities to objectively identify and monitor pain can help determine how to evaluate the techniques used to treat it.

Central to their effort to quantify pain, said Dr. Finkel, the chief of pain medicine here, is a squat, rectangular black box with three eyes peering up from below the screen. It was a Kinect, a motion sensor device that allows users to control games using gestures and spoken commands.

More important for Dr. Finkel was the device's tracking of 24 points on Reilly's body in three dimensions, feeding data about his movements — angles, distance, speed, frequency — to a secure database. Custom software measures his heart rate and converts all of the data to graphics that a physical therapist can see on a tablet computer in real time.

"Since it's digital information, we can manipulate it, understand it, analyze it," Dr. Finkel said. "So from a research perspective, it's a treasure trove of information that would help us formulate new metrics in order to treat these patients."

Danica Zimmerman, 14, saw more than 20 doctors for the burning pain that started last year in her right hand and quickly spread to her other limbs. Many of the doctors told her that the pain, which forced her to quit swimming and refuse hugs, was all in her head. She finally received a diagnosis of reflex sympathetic disorder, another name for chronic regional pain syndrome.

As Danica walked around the complex recently, wearing smiley-faced pajama pants and attached to an IV containing ketamine, she stopped to play a game of Meteor Bounce.

Dr. Rebstock, the director of the complex, said it was normal for her teenage patients to see a handful of doctors before getting the right diagnosis. The National Academies estimates that about 100 million adults in the United States suffer from chronic pain; hospital officials say that between a quarter and a half of children under 18 experience chronic pain lasting more than three months.

"Physicians don't often recognize pain as a pathology," Dr. Rebstock said. "And so patients end up seeing a lot of doctors trying to figure out what's wrong."

The measures developed using the Kinect data could help reduce errors and could easily apply to pain treatment for adults, and even for other chronic conditions like autism, cancer and diabetes, Dr. Rebstock said.

Microsoft released the Kinect for Windows last year as the company was encouraging researchers to explore health applications for the device, which was originally created for the Xbox game console.

Using technical data to assess and treat pain could allow clinicians to replace current methods that Dr. Finkel said were trial and error. Current therapy relies on the patients and doctors to gauge pain by feelings and observations.

The games draw on techniques from physical therapy and yoga to distract children from their pain, but also to increase their range of motion and strength. Clinicians will be able to use initial measurements to determine a baseline range of motions that each patient can perform in pain. By looking at how patients' movements change over time, doctors will be able to determine whether a therapy works.

Dr. Hamid Ekbia, a research professor at Indiana University Bloomington, is developing a game system for stroke patients that would automatically document, maintain and analyze data on the patient's condition and treatment. The option of in-home treatment would provide increased access to care and a way around insurance restrictions that cap therapy sessions at about 15 to 20 visits, limits that leave patients on their own after a few weeks, he said.

"If we can capture this data that shows the progress of the patient, and allow the therapist to document how the patient is doing and even generate automatic reports, that's going to provide a lot of savings of money and time," Dr. Ekbia said.

For the technology to really progress, he said, insurers and lawmakers must change policies to cover the cost of the consoles and to reimburse clinicians for time spent looking over patients' data.

"Our fear is that we will develop all of this and finally we'll hit this policy barrier or this reimbursement barrier," Dr. Ekbia said. "And people might not be able to pick this up just because of those barriers."

The clinicians at Children's National Medical Center are working with developers from Interface Media Group to modify the game system for patients to buy and use at home. Relying on motion tracking and Internet cloud services, physical therapy administered through game consoles would allow clinicians to develop personalized exercise routines based on a patient's condition.

"It's just like your iPhone," Dr. Rebstock said. "Generation one wasn't nearly as cool as whatever we have now. So this is generation one."

Tuesday, April 16, 2013

Opioids are in crisis. Many physicians and patients say that the medications can be used responsibly to treat chronic pain. Yet experts also warn that prescriptions are out of control and fueling an epidemic of abuse, overdose, and death.

Government agencies have responded with tighter regulations, but investigators say the only real solution is to identify the most suitable candidates for opioid treatment: those patients most likely to experience effective analgesia with minimal adverse consequences.

In a recent paper, a panel of prominent pain researchers and clinicians outlines a research agenda for achieving personalized opioid prescribing. Central to that plan is a call for large, long-term observational studies aimed at finding associations between patient characteristics and treatment outcomes. In particular, the panel zeroes in on "practice-based evidence" (PBE), an approach that depends on registry systems that log comprehensive information about large numbers of patients over the course of routine care. After collecting an abundance of data, researchers can comb through the information for factors that associate with outcomes.

"There's a raging question: Who are the people who benefit from long-term opioid therapy?" said Charles Inturrisi, Weill Cornell Medical College, New York, US, who has launched a registry study that is seen as a pilot project for practice-based studies in pain. "Some people would argue, no one. Some would argue, lots of people. Does it make any difference whether you have a cancer pain diagnosis, or a rheumatoid diagnosis, or a spinal stenosis diagnosis?" These are all questions that researchers can begin to address with practice-based data, Inturrisi said.

The paper, written by Inturrisi and other US pain experts, stemmed from a September 2011 US National Institutes of Health (NIH) workshop, "Pathways Toward Evidence-Based, Personalized Analgesic Medication," organized by the National Institute on Drug Abuse (NIDA). The paper appeared in the February issue of the Journal of Pain.

In search of solutions

Evidence for harm from opioid use is accumulating. For example, researchers from the US Centers for Disease Control and Prevention reported recently that US drug overdose deaths increased for the eleventh consecutive year in 2010; roughly half involved prescription opioids (Jones et al., 2013). Furthermore, epidemiological studies of long-term opioid use have yielded "clear, overwhelming evidence of lack of safety: high death rates, high fracture rates, high rates of cognitive dysfunction, and high rates of abuse, particularly in patients who get to high doses," said Jane Ballantyne, University of Washington, Seattle, US, an author on the new paper. In addition, whether or not long-term opioids actually relieve chronic non-cancer pain is controversial, with numerous expert panels concluding that the existing evidence base is too weak to provide an answer (see Chou et al., 2009; Chapman et al., 2010;Reid et al., 2011).

Ballantyne said the existing data, and her own clinical experience, make it look unlikely that long-term opioid therapy is effective and safe. But she accepts that she may not have the whole picture—and she wants more information. "When we try to put controls on opioid use … physicians will stand up and say, 'I've got patients who are doing really well'" on long-term opioid therapy, she said. "But nobody knows who [those patients] are and how to identify them so that you don't start people on opioids who become the patients who do so badly in the long term."

And the need for personalized information is not limited to opioids, Inturrisi said. For many pain treatments—anticonvulsants, tricyclic antidepressants, and others—"they on average only work in about a third of patients. But we don't know which third."

Ballantyne and others say the best hope for obtaining that kind of information is through large observational studies of patients during routine practice—the PBE model.

The approach offers certain advantages over randomized controlled trials (RCTs). Two are time and size: RCTs are so expensive that they are generally small and short, enrolling a limited number of patients and ending in a matter of weeks. Registry studies can follow large numbers of patients for months or years, allowing a fuller look at long-term treatment in multiple patient subgroups.

Another advantage is that the PBE studies look at real-world patients, in all of their complexity. In an RCT of an analgesic, "you exclude everybody who has a history of drug abuse, everyone that has any kind of comorbidity, like [poor] renal function, a history of depression … I could go down the list," said Inturrisi.

A pilot project

In pursuit of personalized pain medicine, Inturrisi struck up a collaboration with Susan Horn, a statistician at the Institute for Clinical Outcomes Research in Salt Lake City, Utah, US, who had already used the PBE approach in other settings, including stroke and spinal cord injury rehabilitation (see Horn et al., 2012; Horn and Gassaway, 2010). But the model was new to pain.

In July 2011, with support from NIDA, Horn and Inturrisi launched the New York City Tri-Institutional Chronic Pain Registry. The registry enrolls all patients from two pain clinics at Memorial Sloan-Kettering Cancer Center; a clinic at New York-Presbyterian/Weill Cornell that sees patients with neuropathic and other forms of non-cancer pain; and the Hospital for Special Surgery (a hospital for orthopedic and rheumatoid conditions). "We have the whole spectrum of pain patients," Inturrisi said, "who have all the comorbidities that come along with being real-world patients."

When a patient comes to one of the clinics, the registry system "talks" to the patient's electronic medical record to collect demographic data like age and sex, diagnoses and comorbidities, and medical and social history. Then, the system tracks all of the treatments the patient receives—medications as well as surgical procedures, physical therapy, cognitive-behavioral therapy, or complementary and alternative therapies. And before every appointment, the patient uses an iPad to answer questions about outcomes including pain, function, adverse events, and red flags for opioid abuse.

The registry-based approach is "integrated into the actual practice of care," Horn said, since information is collected as doctors see patients during clinical care. That means she and her colleagues had to design systems in which physicians and patients can record information in ways that are practical for them and that also are useful for research. "The problem with most clinical information systems today is that, other than lab values and vital signs, almost everything else is text, which means that you have to read it manually," she said. With standardized formats for recording clinical information, researchers can easily capture and compare data among patients. "If you standardize the documentation," then these practice-based studies "can just flow right out," Horn said.

Thus far, the New York registry has enrolled almost 2,000 patients. Currently, all of them come from pain clinics at research hospitals. But Inturrisi wants the registry to capture a fuller range of patients by going into community-based clinics around the city, and eventually into primary care. "That's where 90 percent of pain is being managed," he said.

Moving forward

Inturrisi said that the PBE approach, which is limited in its ability to infer causality, is not a replacement for RCTs. "Ultimately, it will be important to validate [results from PBE studies] with the gold standard—the randomized controlled trial," he said.

But the PBE strategy could help "narrow down the universe of predictors" of opioid response, said Stephen Bruehl, Vanderbilt University School of Medicine, Nashville, Tennessee, US, lead author on the paper.

For instance, Inturrisi and his colleagues are seeking funding to perform genomic analyses on some of the patients in their registry to look for gene variants that associate with drug effects. Inturrisi also said metabolomics analyses might reveal differences in the way patients metabolize drugs and factors that predict drug response. And brain imaging, although too expensive to perform routinely, might help to characterize certain patient subsets and find patterns that predict opioid response, or that could serve as objective measures of analgesia.

"The cost of capturing these biomarkers will continue to drop, so we will be able to capture larger and richer datasets on our patients," said Sean Mackey, Stanford University School of Medicine, California, US, an author on the paper. Mackey is developing another registry platform for patient assessment, based largely on the NIH Patient Reported Outcomes Measurement Information System (PROMIS®), a standardized set of clinical questionnaires that assess patient health and well being. Mackey and his colleagues at Stanford rolled out their system to new patients in August 2012. Currently, the project's aim is to improve clinical care—but in the future, the system should also be useful for research, he said, and he intends to make the platform open source so that other investigators can implement it at their own sites.

For any pain registry study, developing suitable informatics tools is a major challenge, said Jörn Lötsch, Goethe Universität, Frankfurt am Main, Germany, who has studied genetic factors associated with opioid response but was not involved in the NIH workshop or paper. Lötsch's group and others are trying to develop the sophisticated tools needed to crunch the data. "What we get in a complex trait such as pain is high-dimensional data"—information on pain mechanisms, patient characteristics, treatment combinations, genetics, biomarkers, and more. "And we still have not developed the means to deal with high-dimensional data."

Will registry-based studies actually reshape opioid prescribing?

The goal of the PBE approach when it comes to opioids is to pinpoint the patients most likely to experience good pain relief with few side effects and a low risk of abuse. Will Inturrisi and others achieve that aim?

Preliminary data from the New York registry, Inturrisi said, suggest that some patients do benefit from long-term opioids. "The possibility that no one benefits from opioids—I would say that's a bit of a longshot," he said. For those deemed unlikely to do well, physicians could then consider other treatments.

Still, the predictors of individual success with opioid treatment are unknown—and likely numerous. "Is [the predictor] diagnostic code? Is it demographics? Is it concurrent treatments? My guess is it's going to be multifactorial, because I don't think there's a single factor that will predict a particular outcome for our patients," Inturrisi said.

For two decades, the leading theory of phantom limb pain has been that this condition is caused by "maladaptive plasticity." When the brain's primary sensorimotor cortex no longer receives input from a missing body part, such as an amputated hand, signals from another body part, such as the lips, begin to take over that area. Although other phenomena might also be involved, that remapping has largely been thought to cause phantom pain. Tamar Makin from Oxford University, UK, and colleagues challenge that orthodoxy in a paper published March 5 in Nature Communications. They find that amputees who experience ample phantom pain have stronger rather than weaker cortical representations of the missing body part, and no evidence of remapping.

"This is truly significant work, which challenges previous views—close to axiomatic—that phantom limb pain is a marker of cortical reorganization," said Peter Brugger, a phantom limb pain expert at University Hospital, Zurich, Switzerland, who was not involved in the research. It "investigated the cortical correlates of phantom limb pain in the area of the lost limb representation, and not, as all previous work did, changes in the representation of neighboring parts that are still present." Given the findings, it's not surprising, he said, that the success of treatments for phantom pain that are based on maladaptive plasticity has been limited.

Phantom pain is not trivial. An estimated 80 percent of amputees experience phantom pain, which in some cases can be "hugely debilitating," and can continue for years, said Makin. Treatments, including drugs, neuromodulation, surgery, and other approaches are largely ineffective (for a review, see Knotkova et al., 2012).

"The support for the hypothesis of maladaptive plasticity has come primarily from non-invasive functional neuroimaging studies over the past two decades that have noted a shift in the cortical representation of the lip," said Scott Frey, who studies the effects of amputation and limb paralysis on brain organization at the University of Missouri, Columbia, US, and who was not involved in the current study. "This finding has been interpreted as evidence that the face area is expanding into the former hand territory." That remodeling is thought to be the source of phantom pain (for a review, see Flor et al., 2006).

But the theory never appeared quite right to Makin. That, she said, led her to conduct the current study. "It didn't make sense that shifted cortical representation of the face towards the hand area, as has been documented, could trigger pain," she said. Maladaptive plasticity predicts that "following loss of sensory input, the deprived hand area of the primary sensorimotor cortex becomes responsive to inputs from neighboring cortical areas, for example, the face area, thereby triggering phantom pain. The maladaptive plasticity model would therefore predict that representations of the missing hand should be reduced in the sensorimotor cortex of people who suffer from more pain, owing to greater remapping."

But Makin and her co-investigators found the opposite: They found that greater pain in amputees correlated with greater preservation of representation of the hand within its cortical area, as seen in functional MRI (fMRI) scans. Additionally, fMRI scans taken while amputees and two-handed control subjects smacked their lips showed no difference, on average, in cortical activation in the hand area between the two groups, suggesting that cortical representation of the lips was not invading amputees' missing-hand cortices. Nor was activation during lip movement associated with pain intensity among the amputees.

Experiments examining cortical activity during phantom hand movement further challenged the maladaptive plasticity theory. Interestingly, amputees can "move" their phantom limbs to varying degrees, meaning "they are capable of voluntarily inducing the sensation of moving the missing hand," said Frey. That is different from imagining moving a limb—phantom or real—in terms of the sensation evoked, and the activity generated within the cortex.

In these experiments, the researchers compared cortical activity in amputees who moved their phantom hands with cortical activity evoked when two-handed control subjects moved their dominant or non-dominant hands. They found that the fMRI scans of phantom movement were similar to those of two-handed controls moving their non-dominant hands. In fact, when amputees moved their phantom hands, the scans showed that motor execution signals occurred within the cortex as if subjects were moving a real hand. This suggests that representation of the hand was preserved within the cortex in the amputees.

Moreover, contrary to the theory of maladaptive plasticity, the investigators found that greater chronic phantom pain correlated with the degree of activation within the hand cortex, and maintenance of its structural integrity. That finding raises the question of whether chronic phantom pain helps maintain hand cortical structure.

Furthermore, compared to amputees with less phantom pain, amputees with more phantom pain also exhibited less functional connectivity between the cortex for the amputated hand and the cortex for the intact hand, which the investigators suggested results from a lack of co-activation between the two hand cortices.

For his part, Frey criticizes the maladaptive plasticity theory and the studies that support it, noting among other things that one can't tell whether cortical remodeling causes the pain, or whether pain drives the remodeling. But he said that same problem applies to Makin's paper, too: Is cortical representation of the missing hand maintained by pain signals, as Makin suggests, or is it "somehow maladaptive, and driving these experiences?" Frey asked. Frey also suggested that "apparent differences between these findings and those of earlier studies might be, in part, attributable to differences in the fMRI tasks and/or the ways that pain perceptions have been quantified." But he still praised the quality of the study, saying, "It raises important questions that will be important to replicate in additional samples and studies."

Even Herta Flor of the University of Heidelberg, Germany, and a leading proponent of maladaptive plasticity, lauded the quality of Makin's research.

Nonetheless, the problem of where in the body phantom pain arises remains unsolved, a problem that neural plasticity expert Michael Merzenich, University of California, San Francisco, US, finds "terribly frustrating…. Understanding the neurological basis of emergent pain qualia is key to understanding why pain emerges following massive deafferentiation [loss of incoming signals from the now-missing hand or limb] and/or whatever plastic adjustments do/do not follow it."

Meanwhile, based on her current work, Makin is running a double-blind, placebo-controlled, Phase 1 clinical trial of transcranial direct current stimulation for phantom limb pain in hopes that the procedure will provide much-needed relief for patients.

David C. Holzman writes on science, medicine, energy, and the environment from Lexington, Massachusetts, US.

Saturday, April 13, 2013

How do acute painful bouts of inflammation progress to chronic, intractable pain? Identifying the molecular basis of that transition—and how to stop the process—is critical to understanding, and treating, many chronic pain conditions.

A new study from Erica Schwartz, Gerald Gebhart, and colleagues at the University of Pittsburgh School of Medicine, Pennsylvania, US, shows that in a mouse model of recurrent pancreatic inflammation, the transition from acute inflammation to chronic organ damage and pain involves a switch from transient neuroinflammation driven by TRPV1 and TRPA1 channels on sensory neurons to a later, lasting pain state that is impervious to treatment with TRP inhibitors.

The work suggests that in mice subjected to repeated inflammatory insults "there is a transition point" in the molecular mechanisms driving inflammation and pain, Gebhart said. "There are some players that are involved in the beginning … but not after some critical point."

The results raise the possibility that, in people, early treatment with inhibitors of the TRPV1 and TRPA1 channels might help to block the development of chronic pancreatitis. Later treatment, however, may have little effect.

While the study focused on pancreatitis, the results may bear on other painful inflammatory conditions such as inflammatory bowel disease or arthritis, said Rodger Liddle, a gastroenterologist at Duke University Medical Center, Durham, North Carolina, US, who was not involved in the study. "It is important from the standpoint of understanding how chronic pain develops—how does that occur? The paper provides some insights into that mechanism and the timing of some of the events that lead to chronic pain."

The study appeared in the March 27 issue of the Journal of Neuroscience.

A mysterious transition

Pancreatitis arises when digestive enzymes destined for the small intestine prematurely activate in the pancreas, leading to inflammation and pain. In many cases, the condition is transient. But some patients go on to develop a chronic form of the disease, which can be extremely painful. "There are people who have chronic, debilitating pain that is almost uncontrollable. It can be devastating," Liddle said.

Studies in animal models have indicated that changes in primary sensory neurons play a major role in pancreatitis pain. In the initial stages, inflammatory mediators in the pancreas ramp up nociceptor activity. Then the neurons exacerbate the situation by releasing their own inflammatory neuropeptides into the pancreas. Liddle and others have shown that TRP channels contribute to this process, called neurogenic inflammation (Nathan et al., 2001). Recently, Schwartz and colleagues showed that treatment of mice with antagonists of TRPV1 and TRPA1 could reverse inflammation and pain in a mouse model of acute pancreatitis induced by injection of the peptide caerulein (Schwartz et al., 2011).

In the new study, the investigators set out to model repeated bouts of pancreatic inflammation, to ask how that might lead to chronic pancreatitis, and chronic pain. Schwartz said, "We wanted to see why pain, inflammation, and all the parts of the disease progress"—to a point where, in patients, the disease becomes increasingly difficult to treat.

To simulate recurrent acute pancreatitis in mice, Schwartz and colleagues administered caerulein repeatedly, twice a week for 10 weeks. For the first two weeks, immune cell infiltration was only modestly elevated (when measured 72 hours after caerulein injection). But following three weeks of injections, persistent inflammation and organ damage increased dramatically. Pancreatic tissue showed extensive inflammatory infiltrate, atrophy, necrosis, and increased sprouting of sensory nerve fibers—changes similar to those seen in samples from people with chronic pancreatitis. In pancreatic sensory neurons, the investigators saw a sustained increase in expression of TRPV1 and TRPA1, and enhanced excitability. Alongside these changes, the animals showed increased pain behaviors (measured by changes in spontaneous activity and rearing), which reached a plateau at about three weeks.

To see whether TRPV1 and TRPA1 mediated the changes induced by repeated inflammatory insult, the researchers treated the animals weekly with TRPV1 and TRPA1 antagonists (A-889425 and A-967079, both from Abbott Laboratories). They found that inhibiting the channels could reduce inflammation, organ damage, hyperinnervation, channel expression, neuronal excitability, and pain behaviors. But the timing mattered. TRP-blocking treatments worked if they were started before the third week of caerulein challenge; if treatments were started later, they had little effect.

The results indicated that TRP-driven neurogenic inflammation played a major role in the initial pain and in the onset of chronic painful pancreatic damage. That aligns with previous work showing that TRPV1 inhibition reduced pain in rats with chronic pancreatitis simulated using a single administration of the chemical agent trinitrobenzene sulfonic acid (TNBS) (Xu et al., 2007), and a new study showing that TRPA1 knockout reduced pain and inflammation in a similar model in mice (Cattaruzza et al., 2013).

But the study from Schwartz and colleagues, where persistent pain was brought on by recurrent insults, indicated that after a critical TRP-dependent period—three weeks, in this model—chronic pain was maintained by some other molecular mechanism.

Searching for downstream mediators

The current work was all done in a mouse model, but if the results are confirmed in people, it suggests that early treatment with TRP inhibitors might prevent the onset of chronic pancreatitis. For people known to be at high risk, such as individuals with inherited genetic variants that predispose them to chronic pancreatitis, such a preventive therapy could be useful, Liddle said. But both he and Schwartz said that, based on the results in mice, TRP inhibitors might not help patients whose pancreatitis has already become chronic. "For most people we see in the GI clinic who have chronic pancreatitis, they're not going to benefit," Liddle said.

Schwartz is now looking for the molecular changes that sustain chronic pancreatitis in the mouse model, and that might present targets for treatment of later-stage disease. In the current paper, she showed that repeated caerulein challenge increased activation of MAP kinase (MAPK) signaling in nociceptive sensory neurons, indicated by increased phosphorylated ERK (pERK) immunoreactivity. And in preliminary experiments, she said, she has found that ERK inhibition can block pain at later timepoints. She is also looking at downstream targets of MAPK signaling, such as voltage-gated ion channels, to see whether they are upregulated at later stages.

Moving forward, Schwartz said she would like to look at the basis for acute-to-chronic transitions in other visceral diseases such as colitis or cystitis. But a major barrier is a lack of models. Generally, she said, laboratory models of visceral pain involve a single, highly damaging insult, rather than multiple episodes that over time lead to chronic pain. To catch the transition to chronic pain, "You have to come up with a recurring acute inflammatory model that progresses into chronic inflammation." Currently, she said, "There's just not a lot out there."

Further, Gebhart said, researchers may want to examine repetitive inflammation in other tissues—including skin, muscles, and joints—where acute insults seem to prime the system for chronic pain, and where animal models involving a single insult already exist. "If you repeat the stimulus or the inflammation, you may find that the players change." Identifying those late-stage mediators, he said, "could have important therapeutic implications."

Thursday, April 11, 2013

A thermometer is great for measuring a fever, but when it comes to pain, doctors must rely on the age-old question, "How bad is it?" Scientists have long struggled to find physiological signs that can reliably tell "ouch" from "@#%!" and everything in between. Now, a brain scanning study suggests that painful heat excites a specific pattern of neural activity that could hold the key to better diagnosis and treatment of all kinds of pain in the future.

Functional magnetic resonance imaging (fMRI) studies have shown that certain areas of the brain—including the anterior cingulate cortex, somatosensory cortex, and thalamus—activate when people experience pain. But those same regions also light up in response to other experiences, such as painful thoughts or social rejection. In recent years, scientists have looked for a particular pattern of activity across these areas that single out the experience of physical pain. "What we're evolving towards is trying to predict quantitatively from patterns of brain activity how much an individual is feeling," says Tor Wager, a neuroscientist at the University of Colorado, Boulder.

In the new study, Wager's group performed fMRI brain scans on a total of 114 healthy participants while delivering different amounts of heat to the volunteers' arms with a computer-controlled hot plate. In an initial experiment, the scientists used data from 20 people to find a brain-wide pattern of excitation and inhibition—a neural "signature"—that changed reliably as people experienced varying degrees of heat, ranging from painless to scalding. In the remainder of the study, Wager and his colleagues were able use the signature derived from the first group to predict pain responses in a completely different set of subjects—a promising sign for one day using such a model on patients suffering from unknown conditions, he says.

The strength of the signature response scaled with increasing temperatures and correlated well with each person's reports of increasing pain as researchers cranked up the temperature from a toasty but painless 44.3°C to a scalding 49.3°C—akin to a hot cup of coffee, Wager says. Based solely on the intensity of the signature,the team could distinguish whether participants had experienced painful heat or nonpainful warmth with 93% accuracy. The neural reading could also predict which of two painful temperatures hurt more for the subjects, as reported today in The New England Journal of Medicine.

When participants received a pain-relieving chemical called remifentanil, the signature response subsided—even during trials in which people believed that they had received a placebo. The volunteers did not show the pain signature response while anticipating a painfully hot sensation or remembering a previous bout of pain. Those responses were also notably absent as people viewed photographs of their recent exes, a painful social experience that activates some of the same brain areas as physical pain.

"This paper is a quantum leap for the field of imaging pain and hopefully the basis for other groups to go forward," says David Borsook, a pain specialist at Boston Children's Hospital and Harvard Medical School. He predicts that brain scans could one day help doctors track patients' symptoms as they try different treatments or assist researchers in comparing the efficacy of experimental pain drugs.

For now, more work is needed to determine how well Wager's methods can distinguish other kinds of pain such as dull, throbbing aches and stabbing pains, says Robert Coghill, a neuroscientist at Wake Forest University in Winston-Salem, North Carolina. "We need some really hard evidence," that the tests can be used broadly, but he says this study makes a good start. "It's definitely a tour de force."

Thursday, April 04, 2013

Many of us hope to find Wi-Fi wherever we go, preferably for free. But some people devote their lives to avoiding Wi-Fi altogether. Sufferers of Wi-Fi syndrome say that the radio waves used in mobile communication cause headaches, nausea, exhaustion, tingling, trouble concentrating, and gastrointestinal distress, among other symptoms. Some of the most afflicted take drastic action. According to the Agence France-Presse, one woman left her farmhouse in southeastern France after the arrival of mobile-phone masts (which, like Wi-Fi, use radio waves) and fled for a cave in the Alps. A handful of others have moved to homes within the United States National Radio Quiet Zone, a vast area of mountainous terrain on the Virginia-West Virginia border, where Wi-Fi, cell phones, and other technologies are severely limited to protect a nearby radio telescope. Scientists have given the syndrome a mouthful of a name: "idiopathic environmental intolerance attributed to electromagnetic fields," or I.E.I.-E.M.F. But no one has found any good evidence that we are at any risk.

Wi-Fi syndrome does, however, make sense in the context of a larger phenomenon: the "nocebo effect," the placebo effect's malevolent Mr. Hyde. With placebos ("I will please" in Latin), the mere expectation that treatment will help brings a diminution of symptoms, even if the patient is given a sugar pill. With nocebos ("I will harm"), dark expectations breed dark realities. In clinical drug trials, people often report the side effects they were warned about, even if they are taking a placebo. In research on fibromyalgia treatments, eleven per cent of the people taking the equivalent of sugar pills experienced such debilitating side effects that they dropped out.

The nocebo effect is not confined to clinical trials. After the 1995 Aum Shinrikyo sarin nerve-gas attack in Tokyo, for example, hospitals were flooded with patients suffering from the highly publicized potential symptoms, like nausea and dizziness, but who had not, it turned out, been exposed to the sarin. This is common in disasters where the agent is invisible, as with chemicals or radiation. At the extreme are the occasional outbreaks of mass symptoms with no discernable physical cause, such as a famous case at a Tennessee high school that was evacuated after a teacher reported a "gasoline-like" smell and feelings of dizziness. About a hundred students and staff were taken to the emergency room, and thirty-eight were kept overnight. An extensive investigation found no evidence of any chemical presence, and researchers have since concluded it was a "mass psychogenic illness."

As for Wi-Fi syndrome, a recent analysis of forty-six studies involving nearly twelve hundred volunteers concluded, similarly, that the signals do not cause the symptoms. In one experiment, researchers in Austria had people spend several nights sleeping in a cocoon of custom-engineered bed netting, but found it made no difference whether or not the netting stopped electromagnetic signals. One careful study of mobile-phone waves found a significant pattern of headaches, but it turned out the headache cluster fell in the control group—those who had not been exposed to signals. (There is also no convincing evidence of a link between cell phones and brain cancer, another common fear.)

I spoke recently with Michael Witthöft, a German scientist who has been looking into medically unexplained syndromes for more than a decade. The results of his latest inquiry, conducted with a colleague at Kings College London, should make any journalist cringe. Witthöft recruited volunteers, gave them a bevy of psychological tests, and then divided them into two groups. He showed one group a BBC broadcast about the "dangers" of Wi-Fi, featuring all the usual tropes of scare TV: ominous music, uncritical interviews, alarmist narration, and jarring cutaways to cell-phone towers. Witthöft showed the second group a program on mobile-phone security. Then each volunteer was brought into a small room, seated in front of a computer, and fitted with an ungainly headband holding a silver antenna described as a "Wi-Fi amplifier." They were told to push a button—a red Wi-Fi symbol flashed on the screen—and wait fifteen minutes.

There was, in fact, no Wi-Fi in operation, but Witthöft still observed dramatic effects. Sitting in the room with the (fake) Wi-Fi caused tingling in fingers, hands, and feet; pressure and tingling in the head; stomachaches; and trouble concentrating. Two of the subjects found the experience so unpleasant that they had to stop before their time was up. (Only the more anxious volunteers who saw the scare TV reacted badly.) Witthöft's work, and a similar experiment just published on wind-turbine complaints, draws a direct line between irresponsible journalism and health problems. Following a first scare, Witthöft told me, some people seem to get caught in cycles of negative reinforcement. They experience physical symptoms, leading them to pay closer attention to how their body feels. Hypervigilance leads them to notice more symptoms—is that a new tingle?—and become more alarmed. They then withdraw in an effort to avoid what ails them, which can lead to depression, which can itself aggravate the symptoms. In the worst case, they might head for the nearest cave.

"Placebo" has come to mean fake, but, as Michael Specter explained in a feature last year, that's not quite right. The effects are real—so real, in fact that some scientists argue that doctors should receive more training in using placebos, and make them a regular part of their practice. Patients given placebos experience biochemical changes that improve their condition. Placebo painkillers activate the body's natural analgesics. Parkinson's placebos prompt the brain to release dopamine; anxiety and depression placebos elicit changes in the areas of the brain that regulate emotion. One particularly remarkable study recruited patients with irritable-bowel syndrome and told them that their treatment would be "pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in I.B.S. symptoms through mind-body self-healing processes." Even though the treatment was a placebo, and even though the patients knew it was a placebo, they showed significant improvement.

With the recognition of the nocebo effect, though, some doctors now speak of an odd ethical dilemma: the Hippocratic Oath dictates "do no harm," but being honest with patients about potential side effects increases the odds that they will experience them. One suggestion is to adopt an ignorance protocol: ask patients for their permission not to tell them about minor drug side effects. A less fraught alternative is for doctors to speak more carefully, working hard to put the negatives into their proper place. If doctors say "the great majority of patients tolerate this treatment very well" before giving a flu shot, patients experience fewer "adverse events." The larger problem lies outside the clinic: the Internet has become a powerful—and, to some, irresistible—nocebo dosing machine. In another day, it took weeks or even months for a person to gather enough reading to become very, very afraid. Now one can achieve a state of dread in a few short hours, surrounded by the comforts of home.